An inhibition study of beauvericin on human and rat cytochrome P450 enzymes and its pharmacokinetics in rats.
Beauvericin is a secondary metabolite natural product from microorganisms and has been shown to have a new potential antifungal activity. In this study, the metabolism and inhibition of beauvericin in human liver microsomes (HLM) and rat liver microsomes (RLM) were investigated. The apparent K(m) and V(max) of beauvericin in HLM were determined by substrate depletion approach and its inhibitory effects on cytochromes P450 (CYP) activities were evaluated using probe substrates, with IC(50) and the (K(i)) values were 1.2 microM (0.5 microM) and 1.3 microM (1.9 microM), respectively for CYP3A4/5 (midazolam) and CYP2C19 (mephenytoin). Similarly, beauvericin was also a potent inhibitor for CYP3A1/2 (IC(50): 1.3 microM) in RLM. Furthermore, the pharmacokinetics of beauvericin in the rat were studied after p.o administration alone and co-administration with ketoconazole, which indicated a pharmacodynamic function may play a role in the synergistic effect on antifungal activity.
Mei
Li
L
Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510663, China. mei_li@gibh.ac.cn
Zhang
Lixin
L
Dai
Renke
R
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D047630:Depsipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D047630:Depsipeptides; D004791:Enzyme Inhibitors; C004456:beauvericin; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole